Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Only a fraction of AMD patients progress to advanced disease and ophthalmologists cannot predict which patients will advance. Objective molecular markers are needed for clinical prognostics to prevent or slow vision loss. Genomic markers alone are insufficient as many individuals carrying AMD risk genotypes never develop impaired vision. Diverse mechanisms drive AMD progression and multiple biomarkers are needed for optimized patient care. Our long-term goal is the development of molecular technology for assessing AMD risk and monitoring AMD therapeutics. We propose two exploratory proteomic aims that will lead to the development of a panel of AMD protein biomarkers. In aim 1, we will test the hypothesis that proteins altered in macular AMD Bruch's membrane choroid complex provide plasma biomarkers of AMD risk. We have already identified 99 protein biomarker candidates in AMD macular tissues, and will validate these candidates in plasma by targeted LC MS/MS quantitative proteomics. In aim 2, we will test the hypothesis that the aqueous humor (AH) proteome offers new insights to AMD mechanisms and biomarkers. AMD altered proteins will be at higher concentrations in AH than in plasma and more readily detectable. AH and blood specimens will be obtained from cataract surgeries. Global quantitative proteomic analysis of AH will be pursued by LC MS/MS iTRAQ technology. Results will facilitate targeted quantitative proteomic analyses in plasma as AMD altered proteins in both Bruch's choroid and AH likely will provide high AMD discriminatory potential in plasma. We have a large AMD plasma repository of genotyped specimens and proteomic results will be correlated with AMD risk genotypes. Other outstanding resources include the experience of the translational investigative team, and a world-class vision research environment. The overall impact will be high as effective biomarkers will transform AMD patient management.